Objective. To define the cytokine and chemokine profile in cerebrospinal fluid (CSF) from patients with neuropsychiatric systemic lupus erythematosus (NPSLE).Methods. Forty-two SLE patients who had been hospitalized because of NP manifestations were studied. Patients were evaluated at hospitalization and 6 months later; a CSF sample was obtained at each evaluation. As controls, CSF from 6 SLE patients with septic meningitis, 16 SLE patients with no history of NP manifestations (non-NPSLE), and 25 patients with nonautoimmune diseases were also studied. Results. CSF levels of the following molecules were significantly increased in NPSLE patients as compared with non-NPSLE and nonautoimmune diseases control patients, respectively: IL-6 (32.7 versus 3.0 and 2.96 pg/ml), IL-8 (102.8 versus 29.97 and 19.7 pg/ml), IP-10 (888.2 versus 329.7 [P not significant] and 133.6 pg/ml), RANTES (3.8 versus 2.5 and 2.2 pg/ml), MCP-1 (401.7 versus 257.9 [P not significant] and 136.9 pg/ml), and MIG (35.4 versus 11.4 and 3.5 pg/ml). Low levels of IL-2, IL-4, IL-10, TNF␣, and IFN␥ were found in all groups. All cytokines and chemokines, except TNF␣, were significantly higher among the SLE patients with septic meningitis than among the NPSLE patients. Six months later and in the absence of NP manifestations, all elevated molecule levels, except RANTES, in patients with NPSLE had decreased significantly, and no differences were noted between the NPSLE and non-NPSLE groups.Conclusion. A central nervous system response composed of IL-6 and chemokines, but not Th1/Th2 cytokines, is associated with NP manifestations in SLE patients.

BackgroundDespite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE).Methodology/Principal FindingsForty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-β2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased.ConclusionIn NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.

Plasma cells (PCs) are responsible for the production of protective antibodies against infectious agents but they also produce pathogenic antibodies in autoimmune diseases, such as systemic lupus erythematosus (SLE). Traditionally, high affinity IgG autoantibodies are thought to arise through germinal center (GC) responses. However, class switching and somatic hypermutation can occur in extrafollicular (EF) locations, and this pathway has also been implicated in SLE. The pathway from which PCs originate may determine several characteristics, such as PC lifespan and sensitivity to therapeutics. Although both GC and EF responses have been implicated in SLE, we hypothesize that one of these pathways dominates in each individual patient and genetic risk factors may drive this predominance. While it will be important to distinguish polymorphisms that contribute to a GC-driven or EF B cell response to develop targeted treatments, the challenge will be not only to identify the differentiation pathway but the molecular mechanisms involved. In B cells, this task is complicated by the cross-talk between the B cell receptor, toll-like receptors (TLR), and cytokine signaling molecules, which contribute to both GC and EF responses. While risk variants that affect the function of dendritic cells and T follicular helper cells are likely to primarily influence GC responses, it will be important to discover whether some risk variants in the interferon and TLR pathways preferentially influence EF responses. Identifying the pathways of autoreactive PC differentiation in SLE may help us to understand patient heterogeneity and thereby guide precision therapy.